Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.

Centre of Reproduction Development and Aging Faculty of Health Sciences University of Macau Macau 999078 China

Department of Clinical Molecular Biology University of Oslo and Akershus University Hospital 1478 Lørenskog Norway

Department of Psychiatry University of Oxford Oxford UK

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Novo Nordisk Research Centre Oxford

The Norwegian Centre on Healthy Ageing Oslo Norway

Zobrazit více v PubMed

Dikic I., Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–364. doi: 10.1038/s41580-018-0003-4. PubMed DOI

Aman Y., et al. Autophagy in healthy ageing and disease. Nat Aging. 2021;1:634–650. doi: 10.1038/s43587-021-00098-4. PubMed DOI PMC

Klionsky D.J., et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2021;1–382 doi: 10.1080/15548627.2020.1797280. PubMed DOI

Ashford T.P., Porter K.R. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12:198–202. doi: 10.1083/jcb.12.1.198. PubMed DOI PMC

Klionsky D.J. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4:740–743. doi: 10.4161/auto.6398. PubMed DOI

Rubinsztein D.C., Shpilka T., Elazar Z. Mechanisms of autophagosome biogenesis. Curr Biol. 2012;22:R29–R34. doi: 10.1016/j.cub.2011.11.034. PubMed DOI

Hansen M., Rubinsztein D.C., Walker D.W. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. 2018;19:579–593. doi: 10.1038/s41580-018-0033-y. PubMed DOI PMC

Gatica D., Lahiri V., Klionsky D.J. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20:233–242. doi: 10.1038/s41556-018-0037-z. PubMed DOI PMC

Klionsky D.J., et al. Autophagy in major human diseases. Embo j. 2021;40:e108863. PubMed PMC

Olsvik H.L., et al. FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting region (LIR) motif required for efficient maturation of autophagosomes during basal autophagy. J Biol Chem. 2015;290:29361–29374. doi: 10.1074/jbc.M115.686915. PubMed DOI PMC

Sahu R., et al. Microautophagy of cytosolic proteins by late endosomes. Dev Cell. 2011;20:131–139. doi: 10.1016/j.devcel.2010.12.003. PubMed DOI PMC

Arndt V., et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010;20:143–148. doi: 10.1016/j.cub.2009.11.022. PubMed DOI

Kaushik S., Cuervo A.M. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018;19:365–381. doi: 10.1038/s41580-018-0001-6. PubMed DOI PMC

Dice J.F. Altered degradation of proteins microinjected into senescent human fibroblasts. J Biol Chem. 1982;257:14624–14627. PubMed

Pfeifer U., Strauss P. Autophagic vacuoles in heart muscle and liver. A comparative morphometric study including circadian variations in meal-fed rats. J Mol Cell Cardiol. 1981;13:37–49. doi: 10.1016/0022-2828(81)90227-3. PubMed DOI

Kroemer G., Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008;9:1004–1010. doi: 10.1038/nrm2529. PubMed DOI PMC

Fang E.F., et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22:401–412. doi: 10.1038/s41593-018-0332-9. PubMed DOI PMC

Lautrup S., Sinclair D.A., Mattson M.P., Fang E.F. NAD(+) in brain aging and neurodegenerative disorders. Cell Metab. 2019;30:630–655. doi: 10.1016/j.cmet.2019.09.001. PubMed DOI PMC

Croteau D.L., Fang E.F., Nilsen H., Bohr V.A. NAD+ in DNA repair and mitochondrial maintenance. Cell Cycle. 2017;16:491–492. doi: 10.1080/15384101.2017.1285631. PubMed DOI PMC

Leidal A.M., Levine B., Debnath J. Autophagy and the cell biology of age-related disease. Nat Cell Biol. 2018;20:1338–1348. doi: 10.1038/s41556-018-0235-8. PubMed DOI

Hartl F.U. Protein Misfolding Diseases. Annu Rev Biochem. 2017;86:21–26. doi: 10.1146/annurev-biochem-061516-044518. PubMed DOI

Lou G., et al. Mitophagy and neuroprotection. Trends Mol Med. 2020;26:8–20. doi: 10.1016/j.molmed.2019.07.002. PubMed DOI

Kocaturk N.M., Gozuacik D. Crosstalk between mammalian autophagy and the ubiquitin-proteasome system. Front Cell Dev Biol. 2018;6:128. doi: 10.3389/fcell.2018.00128. PubMed DOI PMC

Limanaqi F., et al. Promiscuous roles of autophagy and proteasome in neurodegenerative proteinopathies. Int J Mol Sci. 2020;21 doi: 10.3390/ijms21083028. PubMed DOI PMC

Hamacher-Brady A., Brady N.R., Gottlieb R.A. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem. 2006;281:29776–29787. doi: 10.1074/jbc.M603783200. PubMed DOI

Kang R., Zeh H.J., Lotze M.T., Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571–580. doi: 10.1038/cdd.2010.191. PubMed DOI PMC

Shibata M., et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem. 2006;281:14474–14485. doi: 10.1074/jbc.M600364200. PubMed DOI

Lipinski M.M., et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A. 2010;107:14164–14169. doi: 10.1073/pnas.1009485107. PubMed DOI PMC

Fallaize D., Chin L.-S., Li L. Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. Cell Signal. 2015;27:2543–2554. doi: 10.1016/j.cellsig.2015.09.020. PubMed DOI PMC

Lee J.Y., et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. Embo j. 2010;29:969–980. doi: 10.1038/emboj.2009.405. PubMed DOI PMC

Guebel D.V., Torres N.V. Sexual dimorphism and aging in the human hyppocampus: identification, validation, and impact of differentially expressed genes by factorial microarray and network analysis. Front Aging Neurosci. 2016;8 doi: 10.3389/fnagi.2016.00229. PubMed DOI PMC

Fang E.F., et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22:401–412. doi: 10.1038/s41593-018-0332-9. PubMed DOI PMC

Pickrell A.M., Youle R.J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron. 2015;85:257–273. doi: 10.1016/j.neuron.2014.12.007. PubMed DOI PMC

Franco-Iborra S., et al. Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy. 2021;17:672–689. doi: 10.1080/15548627.2020.1728096. PubMed DOI PMC

Evans C.S., Holzbaur E.L.F. Autophagy and mitophagy in ALS. Neurobiol Dis. 2019;122:35–40. doi: 10.1016/j.nbd.2018.07.005. PubMed DOI PMC

Kerr J.S., et al. Mitophagy and Alzheimer's disease: cellular and molecular mechanisms. Trends Neurosci. 2017;40:151–166. doi: 10.1016/j.tins.2017.01.002. PubMed DOI PMC

Fiesel F.C., et al. (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Rep. 2015;16:1114–1130. doi: 10.15252/embr.201540514. PubMed DOI PMC

Hou X., et al. Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease. Autophagy. 2018;14:1404–1418. doi: 10.1080/15548627.2018.1461294. PubMed DOI PMC

Glatigny M., et al. Autophagy is required for memory formation and reverses age-related memory decline. Curr Biol. 2019;29:435–448.e438. doi: 10.1016/j.cub.2018.12.021. PubMed DOI

Bjørkøy G., et al. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181–197. doi: 10.1016/s0076-6879(08)03612-4. PubMed DOI

Ott C., Konig J., Hohn A., Jung T., Grune T. Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts. Redox Biol. 2016;10:266–273. doi: 10.1016/j.redox.2016.10.015. PubMed DOI PMC

Yu Y., et al. The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits. Behav Brain Res. 2017;334:155–162. doi: 10.1016/j.bbr.2017.07.003. PubMed DOI

De Biase D., et al. Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain. BMC Vet Res. 2017;13:102. doi: 10.1186/s12917-017-1028-1. PubMed DOI PMC

Sun N., et al. Measuring in vivo mitophagy. Mol Cell. 2015;60:685–696. doi: 10.1016/j.molcel.2015.10.009. PubMed DOI PMC

Bjedov I., et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46. doi: 10.1016/j.cmet.2009.11.010. PubMed DOI PMC

Fang E.F., et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep. 2017;7:46208. doi: 10.1038/srep46208. PubMed DOI PMC

Harrison D.E., et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–395. doi: 10.1038/nature08221. PubMed DOI PMC

Pyo J.O., et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun. 2013;4:2300. doi: 10.1038/ncomms3300. PubMed DOI PMC

Simonsen A., et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy. 2008;4:176–184. doi: 10.4161/auto.5269. PubMed DOI

Vellai T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature426, 620, doi:10.1038/426620a (2003). PubMed

Kuma A., et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432:1032–1036. doi: 10.1038/nature03029. PubMed DOI

Inoue K., et al. Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol Neurodegener. 2012;7:48. doi: 10.1186/1750-1326-7-48. PubMed DOI PMC

Rana A., Rera M., Walker D.W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci. 2013;110:8638. doi: 10.1073/pnas.1216197110. PubMed DOI PMC

Todd A.M., Staveley B.E. Expression of Pink1 with α-synuclein in the dopaminergic neurons of Drosophila leads to increases in both lifespan and healthspan. Genet Mol Res. 2012;11:1497–1502. doi: 10.4238/2012.May.21.6. PubMed DOI

Rana A., et al. Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat Commun. 2017;8:448. doi: 10.1038/s41467-017-00525-4. PubMed DOI PMC

Hou Y., Song H., Croteau D.L., Akbari M., Bohr V.A. Genome instability in Alzheimer disease. Mech Ageing Dev. 2017;161:83–94. doi: 10.1016/j.mad.2016.04.005. PubMed DOI PMC

Silva M.V.F., et al. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci. 2019;26:33. doi: 10.1186/s12929-019-0524-y. PubMed DOI PMC

Canter R.G., Penney J., Tsai L.H. The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature. 2016;539:187–196. doi: 10.1038/nature20412. PubMed DOI

Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8:595–608. doi: 10.15252/emmm.201606210. PubMed DOI PMC

Prillaman M. Alzheimer's drug slows mental decline in trial - but is it a breakthrough? Nature. 2022;610:15–16. doi: 10.1038/d41586-022-03081-0. PubMed DOI

Becker R.E., Greig N.H., Giacobini E., Schneider L.S., Ferrucci L. A new roadmap for drug development for Alzheimer's disease. Nat Rev Drug Discov. 2014;13:156. doi: 10.1038/nrd3842-c2. PubMed DOI PMC

Sun Y.X., et al. Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease. J Alzheimers Dis. 2014;38:437–444. doi: 10.3233/jad-131124. PubMed DOI

Caccamo A., De Pinto V., Messina A., Branca C., Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci. 2014;34:7988–7998. doi: 10.1523/jneurosci.0777-14.2014. PubMed DOI PMC

Nixon R.A., et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64:113–122. doi: 10.1093/jnen/64.2.113. PubMed DOI

Lin W.L., Lewis J., Yen S.H., Hutton M., Dickson D.W. Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau. J Neurocytol. 2003;32:1091–1105. doi: 10.1023/b:Neur.0000021904.61387.95. PubMed DOI

Pickford F., et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008;118:2190–2199. doi: 10.1172/jci33585. PubMed DOI PMC

Morel E., et al. Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun. 2013;4:2250. doi: 10.1038/ncomms3250. PubMed DOI PMC

Yu W.H., et al. Macroautophagy–a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 2005;171:87–98. doi: 10.1083/jcb.200505082. PubMed DOI PMC

Yu W.H., et al. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol. 2004;36:2531–2540. doi: 10.1016/j.biocel.2004.05.010. PubMed DOI

Nixon R.A. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007;120:4081–4091. doi: 10.1242/jcs.019265. PubMed DOI

Lee S., Sato Y., Nixon R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J Neurosci. 2011;31:7817–7830. doi: 10.1523/jneurosci.6412-10.2011. PubMed DOI PMC

Fraser PE. et al. Presenilin structure, function and role in Alzheimer disease. Biochim Biophys Acta (BBA) - Mol Basis Dis1502, 1-15, doi:https://doi.org/10.1016/S0925-4439(00)00028-4 (2000). PubMed

Cataldo A.M., et al. Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol. 2004;63:821–830. doi: 10.1093/jnen/63.8.821. PubMed DOI

Lee J.H., et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141:1146–1158. doi: 10.1016/j.cell.2010.05.008. PubMed DOI PMC

Tung Y.-T., et al. Presenilin-1 regulates the expression of p62 to govern p62-dependent tau degradation. Mol Neurobiol. 2014;49:10–27. doi: 10.1007/s12035-013-8482-y. PubMed DOI

Reddy K., et al. Dysregulation of nutrient sensing and CLEARance in presenilin deficiency. Cell Rep. 2016;14:2166–2179. doi: 10.1016/j.celrep.2016.02.006. PubMed DOI PMC

Fedeli C., Filadi R., Rossi A., Mammucari C., Pizzo P. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca(2+) homeostasis. Autophagy. 2019;15:2044–2062. doi: 10.1080/15548627.2019.1596489. PubMed DOI PMC

Jiang Y., et al. Lysosomal dysfunction in down syndrome is APP-dependent and Mediated by APP-βCTF (C99) J Neurosci. 2019;39:5255–5268. doi: 10.1523/jneurosci.0578-19.2019. PubMed DOI PMC

Bordi M., et al. Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy. 2016;12:2467–2483. doi: 10.1080/15548627.2016.1239003. PubMed DOI PMC

Sardiello M., et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325:473–477. doi: 10.1126/science.1174447. PubMed DOI

Wang H., Wang R., Xu S., Lakshmana M.K. Transcription factor EB Is selectively reduced in the nuclear fractions of Alzheimer’s and amyotrophic lateral sclerosis brains. Neuroscience Journal. 2016;2016:4732837. doi: 10.1155/2016/4732837. PubMed DOI PMC

Zhang Y.D., Zhao J.J. TFEB participates in the aβ-induced pathogenesis of Alzheimer's disease by regulating the autophagy-lysosome pathway. DNA Cell Biol. 2015;34:661–668. doi: 10.1089/dna.2014.2738. PubMed DOI

Xiao Q., et al. Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Aβ generation and amyloid plaque pathogenesis. J Neurosci. 2015;35:12137–12151. doi: 10.1523/JNEUROSCI.0705-15.2015. PubMed DOI PMC

Song J.-X., et al. A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models. Aging Cell. 2020;19:e13069. PubMed PMC

Yamamoto F., et al. TFEB-mediated enhancement of the autophagy-lysosomal pathway dually modulates the process of amyloid β-protein generation in neurons. Neuroscience. 2019;402:11–22. doi: 10.1016/j.neuroscience.2019.01.010. PubMed DOI

Lauritzen I., et al. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 2016;132:257–276. doi: 10.1007/s00401-016-1577-6. PubMed DOI PMC

Lin X.-X., et al. DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity. Nat Commun. 2018;9:4400. doi: 10.1038/s41467-018-06624-0. PubMed DOI PMC

Lapierre L.R., et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun. 2013;4:2267. doi: 10.1038/ncomms3267. PubMed DOI PMC

Bao J., et al. Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia. Protein Cell. 2016;7:417–433. doi: 10.1007/s13238-016-0269-2. PubMed DOI PMC

Xiao Q., et al. Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. J Neurosci. 2014;34:9607–9620. doi: 10.1523/JNEUROSCI.3788-13.2014. PubMed DOI PMC

Polito V.A., et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med. 2014;6:1142–1160. doi: 10.15252/emmm.201303671. PubMed DOI PMC

Wang H, Wang R, Carrera I, Xu S, Lakshmana MK. TFEB Overexpression in the P301S model of tauopathy mitigates increased PHF1 levels and lipofuscin puncta and rescues memory deficits. eNeuro3, ENEURO.0042-0016.2016, doi:10.1523/ENEURO.0042-16.2016 (2016). PubMed PMC

Schuur M., et al. Cathepsin D gene and the risk of Alzheimer's disease: a population-based study and meta-analysis. Neurobiol Aging. 2011;32:1607–1614. doi: 10.1016/j.neurobiolaging.2009.10.011. PubMed DOI

Steinfeld R., et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78:988–998. doi: 10.1086/504159. PubMed DOI PMC

Wu J.W., et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–1092. doi: 10.1038/nn.4328. PubMed DOI PMC

Martini-Stoica H., et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med. 2018;215:2355–2377. doi: 10.1084/jem.20172158. PubMed DOI PMC

Medina D.L., et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21:421–430. doi: 10.1016/j.devcel.2011.07.016. PubMed DOI PMC

Xu Y., et al. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Mol Psychiatry. 2020 doi: 10.1038/s41380-020-0738-0. PubMed DOI PMC

Decressac M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci U S A110, E1817-1826, doi:10.1073/pnas.1305623110 (2013). PubMed PMC

Tsunemi T. et al. PGC-1α Rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med4, 142ra197-142ra197, doi:10.1126/scitranslmed.3003799 (2012). PubMed PMC

Rocchi A. et al. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLoS Genet13, e1006962, doi:10.1371/journal.pgen.1006962 (2017). PubMed PMC

Nilsson P., et al. Aβ secretion and plaque formation depend on autophagy. Cell Rep. 2013;5:61–69. doi: 10.1016/j.celrep.2013.08.042. PubMed DOI

Nilsson P., Saido T.C. Dual roles for autophagy: degradation and secretion of Alzheimer's disease Aβ peptide. Bioessays. 2014;36:570–578. doi: 10.1002/bies.201400002. PubMed DOI PMC

Vingtdeux V., et al. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. Faseb j. 2011;25:219–231. doi: 10.1096/fj.10-167361. PubMed DOI PMC

Schaeffer V., Goedert M. Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy. Autophagy. 2012;8:1686–1687. doi: 10.4161/auto.21488. PubMed DOI PMC

Zhao Y., et al. Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer's disease. Aging Cell. 2020;19:e13239. PubMed PMC

Tian Y, Chang JC, Fan EY, Flajolet M, Greengard P. Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy. Proc Natl Acad Sci110, 17071-17076, doi:10.1073/pnas.1315110(2013). PubMed PMC

Harold D., et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088–1093. doi: 10.1038/ng.440. PubMed DOI PMC

Jun G., et al. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol. 2010;67:1473–1484. doi: 10.1001/archneurol.2010.201. PubMed DOI PMC

Ando K., et al. Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains. Acta Neuropathol. 2013;125:861–878. doi: 10.1007/s00401-013-1111-z. PubMed DOI

Moreau K., et al. PICALM modulates autophagy activity and tau accumulation. Nat Commun. 2014;5:4998. doi: 10.1038/ncomms5998. PubMed DOI PMC

Lee M.J., Lee J.H., Rubinsztein D.C. Tau degradation: The ubiquitin–proteasome system versus the autophagy-lysosome system. Prog Neurobiol. 2013;105:49–59. doi: 10.1016/j.pneurobio.2013.03.001. PubMed DOI

Ramesh Babu J., et al. Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem. 2008;106:107–120. doi: 10.1111/j.1471-4159.2008.05340.x. PubMed DOI

Caccamo A., et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell. 2013;12:370–380. doi: 10.1111/acel.12057. PubMed DOI PMC

Silva M.C., et al. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons. Nat Commun. 2020;11:3258. <http://europepmc.org/abstract/MED/32591533 doi: 10.1038/s41467-020-16984-1 https://europepmc.org/articles/PMC7320012 https://europepmc.org/articles/PMC7320012?pdf=render> PubMed PMC

Kim S., et al. NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model. Biochem Biophys Res Commun. 2014;454:196–201. doi: 10.1016/j.bbrc.2014.10.066. PubMed DOI

Chesser A.S., Ganeshan V., Yang J., Johnson G.V. Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons. Nutr Neurosci. 2016;19:21–31. doi: 10.1179/1476830515y.0000000038. PubMed DOI

Lautrup S., et al. Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease. Neurochem Int. 2019;129 doi: 10.1016/j.neuint.2019.104469. PubMed DOI

Cummins N., Tweedie A., Zuryn S., Bertran-Gonzalez J., Götz J. Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J. 2019;38:e99360. PubMed PMC

Corsetti V., et al. NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. Hum Mol Genet. 2015;24:3058–3081. doi: 10.1093/hmg/ddv059. PubMed DOI

Pareja-Cajiao M., et al. Age-related impairment of autophagy in cervical motor neurons. Exp Gerontol. 2021;144 doi: 10.1016/j.exger.2020.111193. PubMed DOI PMC

Del Prete D., et al. Localization and processing of the amyloid-β protein precursor in mitochondria-associated membranes. J Alzheimers Dis. 2017;55:1549–1570. doi: 10.3233/JAD-160953. PubMed DOI PMC

Cenini G., Rüb C., Bruderek M., Voos W. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol Biol Cell. 2016;27:3257–3272. doi: 10.1091/mbc.E16-05-0313. PubMed DOI PMC

Mao P., et al. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension. Hum Mol Genet. 2012;21:2973–2990. doi: 10.1093/hmg/dds128. PubMed DOI PMC

Manczak M., Kandimalla R., Yin X., Reddy P.H. Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease. Hum Mol Genet. 2018;27:1332–1342. doi: 10.1093/hmg/ddy042. PubMed DOI PMC

Reddy P.H., et al. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Hum Mol Genet. 2018;27:2502–2516. doi: 10.1093/hmg/ddy154. PubMed DOI PMC

Wang Z.T., et al. Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer's disease as a mitophagy receptor. Aging Cell. 2019;18:e12860. PubMed PMC

Sorrentino V., et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017;552:187–193. doi: 10.1038/nature25143. PubMed DOI PMC

Ye X., Sun X., Starovoytov V., Cai Q. Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains. Hum Mol Genet. 2015;24:2938–2951. doi: 10.1093/hmg/ddv056. PubMed DOI PMC

Martin-Maestro P., Gargini R., Perry G., Avila J., Garcia-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease. Hum Mol Genet. 2016;25:792–806. doi: 10.1093/hmg/ddv616. PubMed DOI PMC

Checler F., Goiran T., Alves da Costa C. Presenilins at the crossroad of a functional interplay between PARK2/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases. Autophagy. 2017;13:2004–2005. doi: 10.1080/15548627.2017.1363950. PubMed DOI PMC

Lazarou M., et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524:309–314. doi: 10.1038/nature14893. PubMed DOI PMC

Du F., et al. PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain. 2017;140:3233–3251. doi: 10.1093/brain/awx258. PubMed DOI PMC

Cen X., et al. Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model. Nat Commun. 2020;11:5731. doi: 10.1038/s41467-020-19547-6. PubMed DOI PMC

Park J.-S., Kim D.-H., Yoon S.-Y. Regulation of amyloid precursor protein processing by its KFERQ motif. BMB Rep. 2016;49:337–342. doi: 10.5483/bmbrep.2016.49.6.212. PubMed DOI PMC

Bourdenx M., et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell. 2021;184:2696–2714.e2625. doi: 10.1016/j.cell.2021.03.048. PubMed DOI PMC

Caballero B., et al. Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell. 2018;17:e12692. PubMed PMC

Wang Y., et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009;18:4153–4170. doi: 10.1093/hmg/ddp367. PubMed DOI PMC

Heckmann B.L., et al. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer's disease. Cell. 2019;178:536–551.e514. doi: 10.1016/j.cell.2019.05.056. PubMed DOI PMC

Ulland T.K., et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell. 2017;170:649–663.e613. doi: 10.1016/j.cell.2017.07.023. PubMed DOI PMC

Fernández Á.F., et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 2018;558:136–140. doi: 10.1038/s41586-018-0162-7. PubMed DOI PMC

Houtman J., et al. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. EMBO J. 2019;38 doi: 10.15252/embj.201899430. PubMed DOI PMC

Takayama S., Xie Z., Reed J.C. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J Biol Chem. 1999;274:781–786. doi: 10.1074/jbc.274.2.781. PubMed DOI

Behl C. Breaking BAG: the co-chaperone BAG3 in health and disease. Trends Pharmacol Sci. 2016;37:672–688. doi: 10.1016/j.tips.2016.04.007. PubMed DOI

Gamerdinger M., et al. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. Embo j. 2009;28:889–901. doi: 10.1038/emboj.2009.29. PubMed DOI PMC

Johnston J.A., Ward C.L., Kopito R.R. Aggresomes: a cellular response to misfolded proteins. J Cell Biol. 1998;143:1883–1898. doi: 10.1083/jcb.143.7.1883. PubMed DOI PMC

Carra S., Brunsting J.F., Lambert H., Landry J., Kampinga H.H. HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2α phosphorylation*. J Biol Chem. 2009;284:5523–5532. doi: 10.1074/jbc.M807440200. PubMed DOI

Seidel K., et al. The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases. Neuropathol Appl Neurobiol. 2012;38:39–53. doi: 10.1111/j.1365-2990.2011.01198.x. PubMed DOI

Krüger U., Wang Y., Kumar S., Mandelkow E.M. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging. 2012;33:2291–2305. doi: 10.1016/j.neurobiolaging.2011.11.009. PubMed DOI

Elliott E., Tsvetkov P., Ginzburg I. BAG-1 associates with Hsc70.Tau complex and regulates the proteasomal degradation of Tau protein. J Biol Chem. 2007;282:37276–37284. doi: 10.1074/jbc.M706379200. PubMed DOI

Lei Z., Brizzee C., Johnson G.V.W. BAG3 facilitates the clearance of endogenous tau in primary neurons. Neurobiol Aging. 2015;36:241–248. doi: 10.1016/j.neurobiolaging.2014.08.012. PubMed DOI PMC

Fu H., et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat Neurosci. 2019;22:47–56. doi: 10.1038/s41593-018-0298-7. PubMed DOI PMC

Renziehausen J., et al. The cleavage product of amyloid-β protein precursor sAβPPα modulates BAG3-dependent aggresome formation and enhances cellular proteasomal activity. J Alzheimers Dis. 2015;44:879–896. doi: 10.3233/jad-140600. PubMed DOI

Bagherniya M., Butler A.E., Barreto G.E., Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res Rev. 2018;47:183–197. doi: 10.1016/j.arr.2018.08.004. PubMed DOI

Andreotti D.Z., et al. Effects of physical exercise on autophagy and apoptosis in aged brain: human and animal studies. Front Nutr. 2020;7 doi: 10.3389/fnut.2020.00094. PubMed DOI PMC

Partridge L., Fuentealba M., Kennedy B.K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov. 2020;19:513–532. doi: 10.1038/s41573-020-0067-7. PubMed DOI

Donati A. et al. Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J Gerontol A Biol Sci Med Sci56, B375-383, doi:10.1093/gerona/56.9.b375 (2001). PubMed

Pifferi F. et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol1, 30 (2018). <http://europepmc.org/abstract/MED/30271916 https://doi.org/10.1038/s42003-018-0024-8 https://europepmc.org/articles/PMC6123706 https://europepmc.org/articles/PMC6123706?pdf=render>. PubMed PMC

Rittig N., et al. Anabolic effects of leucine-rich whey protein, carbohydrate, and soy protein with and without β-hydroxy-β-methylbutyrate (HMB) during fasting-induced catabolism: a human randomized crossover trial. Clin Nutr. 2017;36:697–705. doi: 10.1016/j.clnu.2016.05.004. PubMed DOI

Vendelbo M.H., et al. Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling. PLoS One. 2014;9:e102031. PubMed PMC

Yang L., et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 2016;14:422–428. doi: 10.1016/j.celrep.2015.12.042. PubMed DOI

Pietrocola F., et al. Metabolic effects of fasting on human and mouse blood in vivo. Autophagy. 2017;13:567–578. doi: 10.1080/15548627.2016.1271513. PubMed DOI PMC

Escobar K.A., Cole N.H., Mermier C.M., VanDusseldorp T.A. Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. Aging Cell. 2019;18:e12876. PubMed PMC

Alirezaei M., et al. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;6:702–710. doi: 10.4161/auto.6.6.12376. PubMed DOI PMC

Chen X., Kondo K., Motoki K., Homma H., Okazawa H. Fasting activates macroautophagy in neurons of Alzheimer's disease mouse model but is insufficient to degrade amyloid-beta. Sci Rep. 2015;5:12115. doi: 10.1038/srep12115. PubMed DOI PMC

Müller L., et al. Long-term caloric restriction attenuates β-amyloid neuropathology and is accompanied by autophagy in APPswe/PS1delta9 Mice. Nutrients. 2021;13:985. doi: 10.3390/nu13030985. PubMed DOI PMC

Kim J., Kundu M., Viollet B., Guan K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–141. doi: 10.1038/ncb2152. PubMed DOI PMC

Schwalm C., et al. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J. 2015;29:3515–3526. doi: 10.1096/fj.14-267187. PubMed DOI

Mejías-Peña Y. et al. Effects of aerobic training on markers of autophagy in the elderly. Age (Dordr)38, 33-33, doi:10.1007/s11357-016-9897-y (2016). PubMed PMC

Mejías-Peña Y., et al. Impact of resistance training on the autophagy-inflammation-apoptosis crosstalk in elderly subjects. Aging (Albany NY) 2017;9:408–418. doi: 10.18632/aging.101167. PubMed DOI PMC

Almeida M.F., et al. Effects of mild running on substantia nigra during early neurodegeneration. J Sports Sci. 2018;36:1363–1370. doi: 10.1080/02640414.2017.1378494. PubMed DOI

Jang Y.C., et al. Association of exercise-induced autophagy upregulation and apoptosis suppression with neuroprotection against pharmacologically induced Parkinson's disease. J Exerc Nutrition Biochem. 2018;22:1–8. doi: 10.20463/jenb.2018.0001. PubMed DOI PMC

Zhao N., et al. The effects of treadmill exercise on autophagy in hippocampus of APP/PS1 transgenic mice. Neuroreport. 2018;29:819–825. doi: 10.1097/wnr.0000000000001038. PubMed DOI PMC

Bové J., Martínez-Vicente M., Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12:437–452. doi: 10.1038/nrn3068. PubMed DOI

Miller R.A., et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468–477. doi: 10.1111/acel.12194. PubMed DOI PMC

Watson JP, 2020. (2020, January - 2023, December). Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL). Identifier NCT04488601. [WWW Document]. URL https://clinicaltrials.gov/ct2/show/NCT04488601.

Seshadri SJ, Gonzales MJ, 2021. (2021, August – 2023, December). Rapamycin – Effects on Alzheimer’s and Cognitive Health (REACH). Identifier NCT04629495. [WWW Document]. URL https://clinicaltrials.gov/ct2/show/NCT04629495.

Cassano T., et al. Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. Exp Neurol. 2019;311:88–105. doi: 10.1016/j.expneurol.2018.09.011. PubMed DOI

Jiang T., et al. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease. Pharmacol Res. 2014;81:54–63. doi: 10.1016/j.phrs.2014.02.008. PubMed DOI

Jiang T., et al. Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance. Neuropharmacology. 2014;85:121–130. doi: 10.1016/j.neuropharm.2014.05.032. PubMed DOI

Frederick C., et al. Rapamycin ester analog CCI-779/Temsirolimus alleviates tau pathology and improves motor deficit in mutant tau transgenic mice. J Alzheimers Dis. 2015;44:1145–1156. doi: 10.3233/jad-142097. PubMed DOI

Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne)9, 400-400, doi:10.3389/fendo.2018.00400 (2018). PubMed PMC

Anisimov V.N. Metformin: do we finally have an anti-aging drug? Cell Cycle. 2013;12:3483–3489. doi: 10.4161/cc.26928. PubMed DOI PMC

Cabreiro F., et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–239. doi: 10.1016/j.cell.2013.02.035. PubMed DOI PMC

Anisimov V.N., et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–2773. doi: 10.4161/cc.7.17.6625. PubMed DOI

Martin-Montalvo A., et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192. PubMed DOI PMC

Kobilo T., et al. AMPK agonist AICAR improves cognition and motor coordination in young and aged mice. Learn Mem. 2014;21:119–126. doi: 10.1101/lm.033332.113. PubMed DOI PMC

Andreux P.A., et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nature Metabolism. 2019;1:595–603. doi: 10.1038/s42255-019-0073-4. PubMed DOI

Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci Rep6, 24700-24700, doi:10.1038/srep24700 (2016). PubMed PMC

Fang E.F. Mitophagy and NAD(+) inhibit Alzheimer disease. Autophagy. 2019;15:1112–1114. doi: 10.1080/15548627.2019.1596497. PubMed DOI PMC

Xie C., et al. Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nat Biomed Eng. 2022;6:76–93. doi: 10.1038/s41551-021-00819-5. PubMed DOI PMC

Ryu D., et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22:879–888. doi: 10.1038/nm.4132. PubMed DOI

Eisenberg T., et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22:1428–1438. doi: 10.1038/nm.4222. PubMed DOI PMC

Eisenberg T., et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11:1305–1314. doi: 10.1038/ncb1975. PubMed DOI

Yang X., et al. Spermidine inhibits neurodegeneration and delays aging via the PINK1-PDR1-dependent mitophagy pathway in C. elegans. Aging. 2020;12:16852–16866. doi: 10.18632/aging.103578. PubMed DOI PMC

Fan J., et al. Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway. Oncotarget. 2017;8:17475–17490. doi: 10.18632/oncotarget.15728. PubMed DOI PMC

Madeo F., Eisenberg T., Pietrocola F., Kroemer G. Spermidine in health and disease. Science. 2018;359 doi: 10.1126/science.aan2788. PubMed DOI

Xie C., Aman Y., Frank J., Donate-Lagartos M.J., Gudmundsrud R., Cechova K., et al. In: Autophagy in Health and Disease. Rothermel B., Diwan A., editors. Academic Press; 2021. Autophagic processes in early- and late-onset Alzheimer’s disease.

Fang E.F., et al. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol Med. 2017 doi: 10.1016/j.molmed.2017.08.001. PubMed DOI PMC

Fang E.F., et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10:5284. doi: 10.1038/s41467-019-13172-8. PubMed DOI PMC

Fang E.F., et al. NAD(+) replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 2016;24:566–581. doi: 10.1016/j.cmet.2016.09.004. PubMed DOI PMC

Fang E.F., et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014;157:882–896. doi: 10.1016/j.cell.2014.03.026. PubMed DOI PMC

Fang E.F., et al. A research agenda for ageing in China in the 21st century (2nd edition): Focusing on basic and translational research, long-term care, policy and social networks. Ageing Res Rev. 2020;64 doi: 10.1016/j.arr.2020.101174. PubMed DOI PMC

Fang E.F., et al. A research agenda for aging in China in the 21st century. Ageing Res Rev. 2015;24:197–205. doi: 10.1016/j.arr.2015.08.003. PubMed DOI PMC

Cox LS. et al. Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults. Lancet Healthy Longev1, e55-e57, doi:10.1016/S2666-7568(20)30011-8 (2020). PubMed PMC

Livingston G., et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–446. doi: 10.1016/s0140-6736(20)30367-6. PubMed DOI PMC

Mattson M.P., Arumugam T.V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 2018;27:1176–1199. doi: 10.1016/j.cmet.2018.05.011. PubMed DOI PMC

Long J.M., Holtzman D.M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–339. doi: 10.1016/j.cell.2019.09.001. PubMed DOI PMC

Kingwell K. Turning up mitophagy in Alzheimer disease. Nat Rev Drug Discov. 2019 doi: 10.1038/d41573-019-00035-6. PubMed DOI

Shintani T., Klionsky D.J. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–995. doi: 10.1126/science.1099993. PubMed DOI PMC

Kobro-Flatmoen A., et al. Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy. Ageing Res Rev. 2021;67 doi: 10.1016/j.arr.2021.101307. PubMed DOI

Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease